This invention relates to purines useful for the potentiation of antibiotics, particularly phleomycin and bleomycin.
The preparation and structure of phleomycin and bleomycin is described in the following references:
(i) K. Maeda, H. Kosaka, K. Yagishita, H. Umezawa. J. Antibiot. (Tokyo) 9: 82-5 (1956). "A new antibiotic, phleomycin." PA0 (ii) T. Takita. J. Antibiot. (Tokyo) 12: 285-9 (1959). "Studies on purification and properties of phleomycin." PA0 (iii) T. Ikakawa, F. Iwami, H. Hiranaka, H. Umezawa. J. Antibiot. (Tokyo) 17: 194-9 (1964). "Separation of phleomycin components and their properties." PA0 (iv) H. Umezawa, K. Maeda, T. Takeuchi, Y. Omaki. J. Antibiot. (Tokyo) 19: 200-9 (1966) "New Antibiotics, Bleomycin A & B." PA0 (v) H. Umezawa, Y. Suhara, T. Takita, K. Maeda. J. Antibiot. (Tokyo) 19: 210-15 (1966). "Purification of Bleomycins." PA0 (vi) T. Takita, Y. Muraoka, A. Fujii, H. Itoh, K. Maeda, H. Umezawa. J. Antibiot. (Tokyo) 25: 197-9 (1972). "The structure of the sulfur-containing chromophore of phleomycin, and chemical transformation of phleomycin to bleomycin." PA0 (vii) T. Takita, Y. Muraoka, T. Yoshioka. J. Antibiot. (Tokyo) 25: 755-7 (1972). "The Chemistry of Bleomycin IX. The Structures of bleomycin and phleomycin." PA0 (viii) H. Umezawa. Biomedicine. 18: 459-475 (1973). "Studies on Bleomycin: Chemistry and the Biological Action."
For the purposes of this invention, it is to be understood that references herein to phleomycin apply equally to bleomycin.
Phleomycin is a natural product with a wide range of antibiotic and antitumour activity, but has aroused little interest as a therapeutic agent because of its potential toxicity at effective dosage levels. With a view to taking advantage of the activity of phleomycin, attention has been given to the use of amplifying agents such as caffeine, which might offer a means of reducing phleomycin dosage levels while maintaining high therapeutic effectiveness. Caffeine itself shows nephrotoxicity, and many other amplifying agents which potentiate phleomycin to a high degree are similarly unsuitable either because they are themselves toxic or because they are metabolised in the body before reaching sites where their influence on phleomycin might be useful.
Typical of prior amplifying agents are a number of purine derivatives, particularly derivatives where an alkyl group is present on the C.sub.6, C.sub.8 atom or an imidazole nitrogen atom of the purine skeleton: ##STR2## The toxicity of these prior amplifying agents is found to be reduced by the inclusion of an alkylthio group at the C.sub.2 position but unfortunately the modification does not at the same time reduce their susceptibility to metabolic degradation. The basis of the present invention is the surprising discovery that the problem of metabolic degradation can be overcome by replacing the 2-alkylthio group with a C-substituted-alkylthio group, particularly a 2-carbamoylalkylthio, a 2-cyanoalkylthio or a 2-acylalkylthio group.